Colorectal cancer: summary of NICE guidanceBMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m461 (Published 02 March 2020) Cite this as: BMJ 2020;368:m461
All rapid responses
We appreciate the response from members of the NICE 151 committee clarifying the rationale for their decision making. Much reliance was placed on the analysis of a single retrospective study in which 48 patients had a lung metastasectomy for colorectal cancer.(1) PulMiCC, the only randomised controlled trial (RCT) was dismissed because of its size.(2) This trial included 46 patients in the metastasectomy arm so unless NICE has a prespecified threshold of 47, two fewer patients is not a credible reason for discounting data from the only RCT.
The systematic reviewers stated that the retrospective study was of low quality and high risk of bias which is most definitely correct. The 48 patients selected for surgery had relatively low rates of the well-established bad prognostic characteristics:- >3 metastases (4%), bilateral (19%) multi-lobe (10%) multi-organ (12.5%) and <12 months since primary resection (33%). These adverse prognostic features were all much higher in the 57 patients selected not to undergo metastasectomy: 67%, 65%, 77%, 37% and 49% respectively. There may have been further differences, that were unknown or not recordable, that influenced the decision for or against metastasectomy. The absence of a randomised control group, as is the case in the many other similar studies, means that it is not a good test of the effectiveness of lung metastasectomy, but confirms that patients with a mix of bad prognostic features are likely to die sooner than those with favourable features.
The PulMiCC RCT (dismissed by the committee) had a well -matched control group of 47 patients with a 5-year survival of 30%. Similar survival rates were found in the control arms of the other two trials of local treatment with radiofrequency ablation and stereotactic ablative radiotherapy. The special feature of controlled trials is the control group. That is where we look to see if the treatment made a difference. Why then would you reject an RCT in favour of a non-controlled study which was not much larger? The committee knew that the PulMICC trial data had been analysed and was out for publication, but no enquiry was made to us about the results.
PulMiCC did have recruitment difficulties and only 18% of the 512 patients who gave informed consent to enter the trial were randomised. The DMEC requested an analysis of reasons for them not proceeding to randomisation.(3) In a sample of 155 patients from the three largest recruiting sites we found that among 41 patients who preferred to make their own decision, 19(46%) almost half, chose surveillance not metastasectomy, but of 78, in whom the clinical team overrode randomisation, 77(99%) had surgery. The potentially eligible patients who consented to join the study after receiving comprehensive even-handed information reflected an equipoise that was not eventually shared by their doctors.
The authors describe metastasectomy as a ‘widespread national practice’. Surely it is the role of NICE to question an established practice based on flawed observational evidence and for which the only randomised trial, although small, was large enough to have to have shown the amount of benefit so widely believed.
1. Kim CH, Huh JW, Kim HJ, Lim SW, Song SY, Kim HR, et al. Factors influencing oncological outcomes in patients who develop pulmonary metastases after curative resection of colorectal cancer. Dis Colon Rectum. 2012;55(4):459-64.
2. Milosevic M, Edwards J, Tsang D, Dunning J, Shackcloth M, Batchelor T, et al. Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC): Updated analysis of 93 randomised patients - control survival is much better than previously assumed. Colorectal Dis. 2020.
3. Treasure T, Farewell V, Macbeth F, Monson K, Williams NR, Brew-Graves C, et al. Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial. Trials. 2019;20(1):718.
Competing interests: No competing interests
We would like to thank Macbeth and Treasure for their comments on pulmonary metastasectomy in the NICE guidance on management of colorectal cancer (1). We agree that the evidence for performing metastasectomy is of low quality and commend their efforts in performing a randomised control trial (2).
Unfortunately, the PulMiCC trial was closed after recruiting only 93 out of an intended 300 patients. We therefore feel this study is underpowered and not able to answer the question of whether metastasectomy is beneficial. No clear conclusions can be drawn from the results.
The committee is aware that in the modern era of systemic anticancer therapies the survival of metastatic colorectal cancer is likely to be significantly greater than the 5% survival often quoted in the literature, and this was considered in reaching a weak recommendation in the guideline.
We accept that the NICE recommendations are based on low quality evidence and welcome the authors comments that metastasectomy may not be beneficial. However, we certainly do not feel there is sufficient evidence to change the recommendation to a stronger one in either direction, or indeed to change widespread national practice.
M Shackcloth, N Bromham, M Kallioinen, P Hoskin , R J Davies, on behalf of the Guideline Committee
1. Bromham N, Kallioinen M, Hoskin P, Davies RJ. Colorectal cancer: summary of NICE guidance. BMJ 2020; 368:m461.
2. Treasure T, Farewell V, Macbeth F, Monson K, Williams NR, Brew-Graves C et al. Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial. Trials 2019; 20(1):718.
Competing interests: No competing interests
We read with interest the review of the NICE guidelines on the management of colorectal cancer (BMJ 7th March 2020). In the section on treatment of colorectal pulmonary metastatic disease, the article is misleading. All cardiothoracic surgical units in the UK regularly undertake pulmonary metastatectomy for colorectal carcinoma. Certainly in our unit and probably in all other UK cardiothoracic units colorectal carcinoma is the commonest reason for carrying out pulmonary metastatectomy. In our experience the 5 year survival following potentially curative pulmonary metastatectomy is at least 50% whereas patients managed with chemotherapy have a 5 year survival of around 5%. This may change in future with the introduction of new biological agents for the treatment of colorectal cancer but we feel it is only fair to point out to the BMJ readership that pulmonary metastatectomy by means of lung resection is commonly carried out in the UK and has excellent results in appropriately selected patients.
Competing interests: No competing interests
In the summary of NICE guidance on the management of colorectal cancer (1) there is a recommendation that ‘people with lung metastases suitable for local treatment’ should be considered for ‘metastasectomy, ablation, or stereotactic body radiation’. Although this is a ‘weak’ recommendation, it will increase the already widespread use of these interventions.
The PulMiCC randomised trial which tested the value of pulmonary metastasectomy in colorectal cancer has been published and shows no significant overall survival advantage from intervention (HR 0.82 (95%CI 0.43, 1.56)) (2). Importantly it also showed that the 5-year survival in the well-matched control group, none of whom had metastasectomy, was 29%, far higher than the generally assumed and widely quoted figure of worse than 5%.(3)
The only evidence supporting the NICE recommendation was a retrospective observational study(4) in which control patients had a number of significantly worse prognostic factors and none survived to 5 years. This study was considered at ‘serious’ risk of bias and of ‘very low’ quality by the NICE systematic reviewers - poor evidence on which to base a recommendation which will expose many patients to significant risk of harm. The only randomised trial evidence(2) does not show any benefit from metastasectomy and clearly undermines the general assumption that without intervention few patients survive to 5 years.
NICE should reconsider this recommendation urgently in the light of this and other relevant but more indirect evidence. The NHS should not waste resources on ineffective or unvalidated procedures.
(1) Bromham N, Kallioinen M, Hoskin P, Davies RJ. Colorectal cancer: summary of NICE guidance. BMJ 2020; 368:m461.
(2) Treasure T, Farewell V, Macbeth F, Monson K, Williams NR, Brew-Graves C et al. Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial. Trials 2019; 20(1):718.
(3) Gonzalez M, Poncet A, Combescure C, Robert J, Ris HB, Gervaz P. Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis. Ann Surg Oncol 2013; 20(2):572-579.
(4) Kim CH, Huh JW, Kim HJ, Lim SW, Song SY, Kim HR et al. Factors influencing oncological outcomes in patients who develop pulmonary metastases after curative resection of colorectal cancer. Dis Colon Rectum 2012; 55(4):459-464.
Competing interests: Tom Treasure is the Chief Investigator and Fergus Macbeth is a member of the Trial Committee of the PulMiCC trial